Feeding behavior is an essential action for many living beings including humans. Therefore, if irregularities in feeding behavior occur, disorders, often connected to diseases, will occur in normal life-maintaining activities. Accompanying recent changes of our dietary environment, obesity is now becoming a social problem. In addition, not only is obesity a serious risk factor for life-style diseases such as diabetes, hypertension, and arteriosclerosis; it is also widely known that increased body weight places excessive burdens on joints such as knee joints, causing arthritis and pain. The “diet boom,” etc. show that there is a potentially great percentage of the population hoping to reduce body weight; on the other hand, many cases of feeding problems such as overeating, occurring due to causes such as hereditary neurosis or neurosis due to stress, have been reported.
Therefore, research on and development of agents for preventing or treating obesity, or agents for inhibiting eating, have been vigorously done for a long time. The centrally acting anorectic drug, Mazindol, is now being marketed.
Many appetite control factors such as leptin, have recently been discovered, and the development of anti-obesity agents or anorectic agents which will regulate the functions of these appetite control factors is progressing. In particular, it is known that melanin-concentrating hormone (hereinafter also abbreviated as “MCH”) originates in the hypothalamus and has orexigenic action. In addition, it has been reported that even though the daily behavior of MCH knock-out mice was normal, the amount of feeding by MCH knock-out mice was significantly reduced and their body weights were lighter than those of normal mice [Nature, Vol. 396, p. 670, 1998]. This indicates that, if a MCH antagonist was produced, it can be expected to be an excellent anorectic agent or anti-obesity agent; but at present there are no known compound, especially non-peptide type compounds, which possess MCH antagonistic actions.
On the other hand, the following compounds are known as amine derivatives.
1) JP 10-504315 A describes a compound represented by the formula:
wherein R1 is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalky, COC1-6 alkyl, C1-6 alkoxy, hydroxy, hydroxy-C1-6 alkyl, hydroxy-C1-6 alkoxy, acyl, nitro, trifluoromethyl, cyano, CHO, SR9, SOR9, SO2R9, SO2NR10R11, CO2R10, NR10SO2R11, CONR10R11, CO2NR10R11, CONR10 (CH2)pCO2R11, (CH2)pNR10, R11, (CH2)pCONR10R11, (CH2)pNR10COR11, (CH2)pCO2—C1-6 alkyl, CO2(CH2)pOR10, CONHNR10R11, NR10R11, NR10CO2R11, NR10CONR10R11, CR10═NOR11, CNR10═NOR 11 (wherein R10 and R11 are independently hydrogen, or C1-6 alkyl and p is 1 to 4);    R2 and R3 are independently hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C1-6 alkoxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, hydroxy-C1-6 alkyl, C1-6 alkyl-O—C1-6 alkyl, CO2R10, CONR10R11, NR10R11 (wherein R10 and R11 are independently hydrogen, or C1-6 alkyl);    R4 and R5 are independently hydrogen or C1-6 alkyl;    R6 is hydrogen, halogen, hydroxy, C1-6 alkyl or C1-6 alkoxy;    R7 and R8 are independently hydrogen, C1-6 alkyl, aralkyl or they, together with the nitrogen to which they are attached, may form a 5- to 7-heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen and sulfur which may be substituted;    A is oxygen, S(O)q (wherein q is 0, 1 or 2), CR4═CR5 or CR4R5 (wherein R4 and R5 are independently hydrogen or C1-6 alkyl), or A is NR12 (wherein R12 is hydrogen or C1-6 alkyl);    B is (CR13R14)q (wherein q is 2, 3 or 4, R13 and R14 are independently hydrogen or C1-6 alkyl), or B is (CR13R14)r-D (wherein r is 0, 1 or 2, D is oxygen, sulfur or CR13═CR14); m is 1 to 4; and n is 1 or 2; or a salt thereof, which has 5-HT1D antagonistic activity.
As specific examples thereof, there are described 1-(4′-acetamidomethyl-2′-methylbiphenyl-4-carbonyl)-5-chloro-2,3-dihydro-6-(2-dimethylaminoethoxy)-1H-indole, 1-(4′-acetamidomethyl-2′-methylbiphenyl-4-carbonyl)-2,3-dihydro-6-(3-dimethylaminopropyl)-5-ethoxy-1H-indole, etc.
2) JP 9-506885 A (WO95/17398) describes a compound represented by the formula:
wherein P is a 5- to 7-membered heterocyclic ring containing one to three heteroatoms selected from oxygen, nitrogen and sulfur;    R1, R2 and R3 are independently hydrogen, halogen, C1-6 alkyl, C3-6 cycloalky, C3-6 cylcoalkenyl, C1-6 alkoxy, acyl aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R9, CONR10 R11, NR10R11 (wherein R9, R10 and R11 are independently hydrogen, or C1-6 alkyl);    R4 is hydrogen, halogen, hydroxy, C1-6 alkyl or C1-6 alkoxy;    R5 and R6 are independently hydrogen or C1-6 alkyl;    R7 and R8 are independently hydrogen, C1-6 alkyl, aralkyl or they, together with the nitrogen to which they are attached, may form a 5- to 7-heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen and sulfur which may be substituted;    A is oxygen, S(O)n (wherein n is 0, 1 or 2), or A is NR12 (wherein R12 is hydrogen or C1-6 alkyl), or A is CR5═CR6 or CR5R6 (wherein R5 and R6 are independently hydrogen or C1-6 alkyl);    m is 1 to 4;    n is 1 or 2;    B is (CR13R14)q (wherein q is 2, 3 or 4, R13 and R14 are independently hydrogen or C1-6 alkyl), or B is (CR13R14)r-D (wherein r is 0, 1 or 2, D is oxygen, sulfur or CR13═CR14); or a salt thereof, which has 5-HT1D antagonistic activity.
As specific examples thereof, there are described [7-(2-dimethylaminoethoxy)-6-methoxy-3,4-dihydro-2H-quinolin-1-yl]-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone, [7-(2-dimethylaminopropyl)-6-methoxy-3,4-dihydro-2H-quinolin-1-yl]-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone, etc.
3) JP 6-211800 A describes a compound represented by the formula:
wherein R1 is hydrogen atom, a halogen atom, hydroxy group, a lower alkanoyloxy group, amino-lower alkoxy group which may have a group selected from a lower alkyl group and a lower alkanoyl group as a substituent, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, or an aminocarbonyl lower alkoxy group which may have a lower alkyl group as a substituent; R4 is hydrogen atom, a group of —NR6R7 (wherein R6 and R7 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkenyl group or benzoyl group having a halogen atom on the phenyl ring), a lower alkenyloxy group, a hydroxy-substituted lower alkyl group, a group of —O—CO-ANR8R9 (wherein A is a lower alkylene group, R8 and R9 are the same or different and are hydrogen atom or a lower alkylene group, or R8 and R9, together with the nitrogen atom to which they are attached, may form a 5- to 6-membered saturated or unsaturated heterocyclic ring through or without through oxygen or nitrogen atom, said heterocyclic ring may have a lower alkyl group on the heterocyclic ring as a substituent), a group of —O—R10 (R10 is an amino acid residue), a lower alkoxycarbonyl-substituted lower alkylidene group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a group of -ACONR11R12 (A is as defined above, R11 and R12 are the same or different and are hydrogen atom, a lower alkyl group which may have hydroxy group, piperidinyl group which may have a phenyl-lower alkyl group on the piperidine ring, a carbamoyl-substituted lower alkyl group, a pyridyl-substituted lower alkyl group, pyridyl group, a group of -ANR39R40 (A is as defined above, R39 and R40 are the same or different and are hydrogen atom or a lower alkyl group which may have hydroxy group, or R39 and R40, together with the nitrogen atom to which they are attached, may form a 5- to 6-membered saturated heterocyclic ring thorough or without thorough nitrogen or oxygen atom, said heterocyclic ring may have a lower alkyl on the heterocyclic ring as a substituent), a pyrazinyl-substituted lower alkyl group which may have a lower alkyl group on the pyrazine ring as a substituent, a pyrrolyl-substituted lower alkyl group which may have a lower alkyl group on the pyrrole ring, a pyrrolidinyl-substituted lower alkyl group which may have a lower alkyl group on the pyrrolidine ring, or phenyl group which may have a halogen atom on the phenyl ring, or R11 and R12, together with the nitrogen atom to which they are attached, may form a 5- to 7-membered heterocyclic ring through or without thorough nitrogen or oxygen atom, said heterocyclic ring may be substituted with a lower alkyl group or a pyrrolidinylcarbonyl-lower alkyl group, each of which may have one to two groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, amino group which may have a group selected from the group consisting of a lower alkyl group or a lower alkanoyl group as a substituent, a lower alkoxycarbonyl-substituted lower alkyl group, phenyl group which may have a halogen atom on the phenyl ring, a cyano-substituted lower alkyl group, a lower alkenyl group, an oxiranyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group and amino group which may have hydroxy group and a lower alkyl group as a substituent), a group —OACONR23R24 (A is as defined above, R23 and R24 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, piperidinyl group which may have a lower alkyl group on the piperidine ring, or a group of —B—NR23AR24A (wherein B is a lower alkylene group, R23A and R24A are the same or different and are hydrogen atom or a lower alkyl group, or R23A and R24A, together with the nitrogen atom to which they are attached, may form a 5- to 6-membered saturated heterocyclic ring through or without through nitrogen atom or oxygen atom), or R23 and R24, together with the nitrogen atom to which they are attached, may form a 5- to 7-membered saturated heterocyclic ring through or without through nitrogen atom or oxygen atom, said heterocyclic ring may have a lower alkyl group on the heterocyclic ring as a substituent), a pyrrolidinylcarbonyl-lower alkoxy group having a lower alkoxycarbonyl group on the pyrrolidine ring, a lower alkoxy-substituted lower alkanoyloxy group, a group of —BOCOANR25R26 (A is as defined above, B is lower alkylene group, R25 and R26 are the same or different and are hydrogen atom or a lower alkyl group), amino-substituted lower alkylidene group which may have a lower alkyl group as a substituent, a group of —OANR27R28 (A is as defined above, R27 and R28 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylsulfonyl group, an aminothiocarbonyl group which may have a lower alkyl group as a substituent, a group of
wherein R41 is hydrogen atom or cyano group, R42 is a lower alkyl group or amino group which may have a lower alkyl group as a substituent), carbamoyl group, a lower alkoxycarbonyl group, cycloalkyl group, a phenyl-lower alkyl group which may have a halogen atom as a substituent on the phenyl group, a cyano-substituted lower alkyl group, a halogen atom-substituted lower alkylsulfonyl group or an amino-substituted lower alkyl group which may have a lower alkyl group, or R27 and R28, together with the nitrogen atom to which they are attached, may form a 5- to 10-membered monocyclic or bicyclic, and saturated or unsaturated heterocyclic ring, said heterocyclic ring may have oxo group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group or a lower alkanoylamino group on the heterocyclic ring as a substituent), cyano group, a cyano-substituted lower alkyl group, a lower alkoxy group having phenylsulfonyloxy group whose phenyl ring may have a lower alkyl group as a substituent or hydroxy group, a group -ANR29R30 (A is as defined above, R29 is hydrogen atom or a lower alkyl group, R30 is a lower alkenyl group, cycloalkyl group or a lower alkynyl group, or R29 and R30, together the nitrogen atom to which they are attached, may form a 5- or 6-membered saturated heterocyclic ring through or without through nitrogen atom or oxygen atom, said heterocyclic ring may have a lower alkyl group, a lower alkanoyl group, amino group which may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group, or aminocarbonyl group which may be substituted with a lower alkyl group on the heterocyclic ring as a substituent), a phenylsulfonyloxy-substituted lower alkyl group which may have an lower alkyl group on the phenyl ring, a phthalimide-substituted lower alkyl group, a cyano-substituted lower alkylidene group, a halogen atom-substituted alkyl group, an imidazolyl-substituted lower alkyl group, 1, 2, 4-triazolyl-substituted lower alkoxy group, 1, 2, 3, 4-tetrazolyl-substitued lower alkoxy group, 1, 2, 3, 5-tetrazolyl-substitued lower alkoxy group, 1, 2, 3, 4-tetrazolyl-substituted lower alkyl group, 1, 2, 3, 5-tetrzolyl-substituted lower alkyl group, 1, 2, 4-triazolyl-substituted lower alkyl group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a pyridylthio-substituted lower alkoxy group, a pyrimidinylthio-substituted lower alkoxy group which may have a lower alkyl group on the pyrimidine ring, an imidazolylthio-substituted lower alkoxy group, a pyridylsulfinyl-substituted lower alkoxy group, a pyridylsulfonyl-substituted lower alkoxy group, an imidazolylsulfinyl-substituted lower alkoxy group or an imidazolylsulfonyl-substituted lower alkoxy group; R5 is hydrogen atom or hydroxy group, or R4 and R5 together form oxo group; R2 is hydrogen atom, a lower alkyl group, hydroxy group, a halogen atom or a lower alkoxy group; R3 is a group of
(wherein R13 is a halogen atom, hydroxy group, carbamoyl group, a lower alkyl group, a piperazinyl-lower alkoxy group having a lower alkanoyl group at 4-position of the piperazine ring, an imidazolyl-substituted lower alkoxy group, piperidinyl-lower alkoxy group having a lower alkanoylamino group on the piperidine ring, a 1, 2, 4-triazolyl-substituted lower alkoxy group, a ureido-substituted lower alkoxy group which may have a lower alkyl group or an amino-substituted lower alkoxy group which may have a lower alkyl group as a substituent; m is 0 or an integer of 1 to 3, a phenyl-lower alkanoylamino group which have one to three groups selected from the group consisting of a halogen atom, a lower alkoxy group, a lower alkyl group and nitro group on the phenyl ring as a substituent, a group of
(n is 1 or 2) or a group of
the bond between 4 and 5 positions of the benzazepine ring represent a single bond or a double bond; provided that, when R1 is hydrogen atom or a halogen atom, and R4 is hydrogen atom, a group of —NR6R7 (R6 and R7 are the above R6 and R7 other than benzoyl group having a halogen atom on the phenyl ring as a substituent), a group of —O—COANR8R9 (A is as defined above, R8 and R9 are the same or different and are hydrogen atom or a lower alkyl), a hydroxy group-substituted lower alkyl group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group or a group —O-A-NR27R28 (A is as defined above, R27 and R28 are the same or different and are hydrogen atom or a lower alkyl group), R5 is hydrogen atom or hydroxy group or R4 and R5 together form oxo group, and further R3 is a group of
R13 must be carbamoyl group, a piperazinyl-lower alkoxy group having a lower alkanoyl group at 4-position of the piperazine ring, a piperidinyl-lower alkoxy group having a lower alkanoylamino group on the piperidine ring, 1, 2, 4-triazolyl-substituted lower alkoxy group or a ureido-substituted lower alkoxy group which may have a lower alkyl group; or a salt thereof, which has vasopressin antagonistic activity or oxytocin antagonistic activity.
As specific examples, there are described N-[4-[[7-[3-(dimethylamino)propoxy]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]phenyl]-2-methylbenzamide, etc.
There has been great desire for the development of a melanin-concentrating hormone antagonist which is useful as an agent for preventing or treating obesity, excellent in oral absorbency, and safe.